By using gene therapy to carry into cells the surrogate for a missing protein essential for maintaining muscle integrity, researchers were also able to prolong survival in the mice. They called it a "glimmer of hope" in a report in the Aug. 23 issue and online version of the Proceedings of the National Academy of Sciences.

It was "the first evidence of a successful gene therapy approach that improved both the general health and longevity in mice with congenital muscular dystrophy," said Xiao Xiao Ph.D., and colleagues. But they noted that "we have much farther to go until we can say gene therapy will work in children."

The mice in the study are models for human congenital muscular dystrophies, a family of disorders characterized by severe and progressive muscle wasting and weakness that often leads to death in early childhood.

A key pathology of CMD is the congenital absence of laminin-Î±2, a glycoprotein that protects the integrity of muscle cell structure during repeated cycles of contraction and relaxation. Laminin-2 interconnects myofiber extracellular basal lamina with plasma membrane. In muscle where laminin-Î±2 is missing or weakened, the extracellular matrix disintegrates, leaving the myocytes susceptible to damage.

"Laminin-Î±2-deficient CMD is one of the most severe muscular dystrophies with no effective therapy currently available," the authors noted. "The aggressive pathology of CMD is often so severe that patients die at a very early age and are never able to walk."

Although somatic gene therapy holds promise for treating muscular dystrophies, the gene that expresses laminin-Î±2 is too large to cram into adeno-associated virus (AAV), the preferred vector for carrying therapeutic genes into cells.

So to get around the size problem, Dr. Xiao and colleagues swapped the gene for laminin-Î±2 with a gene that overexpresses a miniature version of chick agrin, a closely related protein that in other studies has shown to offer therapeutic benefits in lamina-Î±2 knockout mice.

They investigated whether two strains of recombinant AAV modified to infect cells and transfer the gene for the mouse "miniagrin" could slow or reverse the muscle wasting effects of laminin-Î±2 deficiency.

They gave modified AAV-1 systemically by via a single abdominal cavity infusion, and modified AAV-2 delivered locally via direct intramuscular injections into different leg muscles.

In both cases, the muscle cells incorporated and copied the gene and began expressing miniagrin, which then assumed the role of the missing laminin-Î±2. Two months after vector administration, when the mice were killed and their tissues examined, the investigators found that the treated mice had "continuous and dense basal lamina structure, immediately outside the myofiber plasma membrane." The muscles appeared similar to those of wild-type mice, the authors wrote.

In addition, laminin-Î±2-deficient mice that were given the recombinant vector systemically had evidence of miniagrin overexpression in the diaphragm, heart and intercostal, abdominal, and limb muscles.

Treated knockout mice also grew faster and were larger than their untreated littermates, although their growth still lagged behind that of wild-type animals. The treated mice were also more active, better coordinated, and they survived significantly longer.

The 50% survival of the untreated dystrophic mice was about four weeks, but the vector-treated mice survival times were quadrupled to about 17 weeks.

"Whereas all of the untreated mice (n=8) had died by 13 weeks after birth, only one of the seven treated mice had died by that time, and the longest lifespan was 35 weeks," the researchers wrote. "These results demonstrated that systemic somatic gene delivery of the miniagrin gene could improve both longevity and general health of the CMD mice."

Chungping Qiao, M.D., Ph.D., a research associate fellow in Dr. Xiao's lab, said "it's probably not realistic to expect that we can achieve complete success using the miniagrin gene, which while somewhat similar, is structurally unrelated to laminin-Î±2. "Unless we address the underlying cause of congenital muscular dystrophy we're not likely to be able to completely arrest or cure CMD."

The authors pointed out that despite the major improvement of muscle morphology and general health in the CMD mice, the efficacy of a somatic gene therapy regimen was still far from ideal. Neonatal treatment delayed the dystrophic phenotypes but failed to completely prevent them. As a result, in utero gene therapy may be required to achieve earlier and possibly better therapeutic effects.

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.